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L eber hereditary optic neuropathy (LHON, MIM 535000) is a mitochondrial genetic disease that causes blindness in young adults, with an estimated prevalence of 1 in 25 000 in the north east of England.1 It classically presents as bilateral subacute loss of central vision owing to the focal neurodegeneration of the retinal ganglion cell layer. There is marked cell body and axonal degeneration, with associated demyelination and atrophy observed from the optic nerves to the lateral geniculate bodies.2,3 Over 95% of cases are principally the result of one of three “primary” mtDNA point mutations, G3460A, G11778A, and T14484C, which all involve genes encoding complex I subunits of the mitochondrial respiratory chain.4 However, only ~50% of male and ~10% of female LHON carriers will develop the optic neuropathy.5 This marked incomplete penetrance and gender bias clearly indicates that additional factors are required for the phenotypic expression of the pathogenic mtDNA mutations in LHON. Segregation analysis initially suggested that a nuclear encoded modifier locus on the X chromosome could account for these intriguing features.6,7 However, attempts to map this X linked susceptibility locus using standard linkage analysis have so far not been successful.8–10 Furthermore, the Bu and Rotter segregation model could not be replicated in every LHON population.11 It is therefore likely that the phenotypic expression of the primary mtDNA LHON mutations is dependent upon the complex interaction of multiple susceptibility factors, which may include nuclear modifier genes and environmental agents.12 There is a strong association between APOE genotype and a number of common neurodegenerative conditions, including Alzheimer disease and dementia with Lewy bodies. The APOE e4 allele is associated with an increased lifetime risk and an earlier age of onset for these …

Genetic factors are important in the aetiology of the two most common neurodegenerative diseases: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).1,2 Individuals with AD are more likely to have a similarly affected mother than a similarly affected father,3 raising the possibility of a maternally transmitted susceptibility factor. Patients with AD accumulate cytochrome c oxidase deficient neurones at a faster rate than age matched controls,4 and although contentious, abnormal mitochondrial function has been documented in the brains of patients with AD. Cybrid studies suggest that the biochemical abnormality is due to a defect of the mitochondrial genome (mtDNA).5 Different mtDNA sequence variants have been associated with AD and DLB, but there have been no consistent findings, and a maternally transmitted susceptibility factor remains elusive. The 16.5 kb mtDNA molecule codes for 13 essential respiratory chain subunits and the 24 RNAs required for intramitochondrial protein synthesis. Transcription and translation of mtDNA is controlled by the short 1 kb non-coding D-loop. In the wild-type genome, a thymidine residue at nucleotide position (np) 16189 interrupts a tract of cytosine residues between np 16184 and 16193, close to the origin of heavy strand replication (OH).6 The presence of a cytosine residue at np 16189 generates a homopolymeric C tract which appears to be unstable. It is thought …